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Sunday, September 11, 2011

Boehringer Ingelheim’s application for a patent on “3-[(2-{4-(Hexyloxycarbonylamino-Imino-Methyl)-PhenylAmino]-Methyl}-1-Methyl-1h-Benzimidazol-5-Carbonyl)-Pyridine-2-Yl-Amino]-Propionic Acid Ethyl Ester Methane Sulphonate and Use Thereof as a Medicament” was rejected by the Delhi Patent Office earlier this year.

Since the reason for the rejection was Section 3(d), I thought it might be worthwhile to take a look at the decision and report a few more decisions on 3(d) rejections by the Patent Office to understand if there’s a pattern in them.

The claimed invention 3-[(2-{4-(Hexyloxycarbonylamino-Imino-Methyl)-PhenylAmino]-Methyl}-1-Methyl-1h-Benzimidazol-5-Carbonyl)-Pyridine-2-Yl-Amino]-Propionic Acid Ethyl Ester Methane Sulphonate was meant to be used for post-operative prophylaxis of Deep Vein Thrombosis (DVT). (Prophylaxis refers to preventive treatment of any health condition)

The invention is derived from the free base form of Ethyl3-[(2-{4-(HexyloxycarbonylaminoImino-Methyl)-Phenyl Amino]-Methyl}-1-Methyl-1h-Benzimidazol-5-Carbonyl)-Pyridine-2-1 Yl-Amino]-Propionate.

This free base form has been referred to in prior art as BIBR-1048 or BIBR-1048 base. Its methanesulphonate salt too is known in the prior art and has been referred to as BIBR-1048MS.

The claimed invention specifically restricts its claim to polymorph II i.e. the crystalline form of BIBR-1048MS.

The question before the Patent office was that, in light of the prior art disclosing the free base BIBR-1048 and its methanesulphonate salt BIBR-1048MS, did the claim over the crystalline form of BIBR-1048MS contain an inventive step?

Did the crystalline form of BIBR-1048MS disclose greater efficacy in treating post-operative DVT which could not have been gleaned from the information already available on the use of the free base and the salt for the condition?

Boehringer submitted to the Patent Office that the water solubility of the free base was 0.003 mg/ml. In contrast, the claimed invention exhibited greater water solubility levels of 1.8 mg/ml. Boehringer also submitted that bioavailability is directly connected to water solubility and since the invention increased the water solubility of the compound, it resulted in increased bioavailability as well.

This argument did not find favour with the Patent Office because it is a known fact that salts exhibit greater water solubility than freebases. The Patent Office on this point observed thus:

“The applicant argued that the methanesulphonate salt of BIBR-I048 shows good solubility in water. However, this is a phenomenon regularly observed with salts, as compared to the free bases (in this case BIBR-I048 as disclosed in D2), and the search for suitable salts of bases is one of the standard procedures in pharmaceutical chemistry. Hence, this difference cannot give rise to an inventive step”

The Patent Office took the view that the specification was bereft of data on stability and moisture absorption when the prior art considered these details critical in the assessment of pharmaceutically active substances.

This document, according to the Patent Office, in fact discloses the crystalline form of BIBR-1048MS whose melting point is 178-179°Celsius. The melting point of the claimed invention was 190±3°Celsius. The Patent Office observed that no evidence had been submitted by the applicant to distinguish the prior art compound from the claimed invention when the characteristics were near-identical.

Dorland’s Illustrated Medical Dictionary was cited by the Office, which defines efficacy as the ability of a drug to produce the desired therapeutic effect and it is independent of potency, which expresses the amount of the drug necessary to achieve the desired effect.

Stating that the applicant had not provided any experimental data on significant enhancement in therapeutic efficacy, besides lack of proof of enhancement of critical properties, the Patent Office rejected the application.

On first blush, this decision appears grounded because the Patent Office seems to have gone through the prior art with a fine-toothed comb. That said, since I am not a person of ordinary skill in the art in field of the invention, I’ll leave it for better informed and trained readers to volunteer with comments on the decision.